ZA200601992B - CRF antagonists and heterobicyclic compounds - Google Patents

Description

® ® DESCRIPTION

CRF ANTAGONISTS AND HETEROBICYCLIC COMPOUNDS

Technical Field

The present invention relates to a Corticotropin Releasing Factor antagonist, a novel bi-heterocyclic ring compound, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, and a pharmaceutical comprising them as an active ingredient. For more detail, the present invention relates to a Corticotropin Releasing Factor antagonist comprising a compound of formula (I):

R! ¢ 1: 3) (shiz). ee

N Zz wherein all symbols are as hereinafter defined; as an active ingredient and a novel bi-heterocyclic ring compound of formula (I-A):

R! on

Qu 5) (I-A)

SEEN

N z: wherein all symbols are as hereinafter defined; a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, and a pharmaceutical comprising them as an active ingredient.

Background Art

Corticotropin Releasing Factor (CRF) was a peptide comprising 41 amino acid residues and isolated from ovine hypothalamic in 1981. It was suggested that CRF was released from hypothalamic and controlled a secretion of adrenocorticotropic hormone (ACTH) from hypophysis [Science, 218, 377-379(1982)].

ACTH, which is released by a stimulation of CRF, stimulates a secretion of cortisol from adrenal cortex, and relates to a systemic action for reproduction, growth, gastrointestinal function, inflammation, immune system, nervous system efc.

Consequently, CRF is believed to plays a role as a regulator of these functions. In view of these, a relationship of CRF and a central nervous system disease or a neuropsychiatric disorder has gotten a lot of attention.

® ® On the other hand, the depression patients and the anxiety disorder patients increase, and the number also of depression patients with the slight illness increases recently. Moreover, an aged patient is commanding a majority in the depression patient.

Under these circumstances, from the earliness of the appearance of the effect and respect of the side effect, psychiatric and neurologic disorders treatment used easily is requested more and more.

Currently, for the treatment of psychiatric and neurologic disorders, for example, tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase inhibitors, serotonin and noradrenaline reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), efc. as antidepressant are used. However, the therapeutic gain is not enough; it will take a long time by the time the effect appears; drowsiness, a dryness of the mouth and constipation and difficulty feelings in micturition efc. are seen as a side effect. As an antianxiety agent, such as benzodiazepine anxiolytic, thienodiazepine anxiolytic, non-benzodiazepine anxiolytic etc. are used. However, the therapeutic gain is not also enough; decrease in mental movement function and decrease in concentration and attention power, drowsiness, stagger, dizziness, headache, amnesia, efc. are seen as a side effect.

It is expected to use a compound having an activity of CRF antagonist for the treatment of depression and anxiety disorders. For example, in pamphlet of WO 02/53565, a compound of formula (A):

RA a

Sy wt

R3A wherein X* and Y* each independently, is carbon or nitrogen and both are not nitrogens at the same time; W* is carbon or nitrogen; U* and Z* each independently, is

CR* NRPA nitrogen, oxygen, sulfur, C=0 or C=S; === is a single bond or a double bond; (aX is C4-6 carbocyclic ring or 4-6 membered heterocyclic ring containing at least one of nitrogen, oxygen and sulfur and these rings are unsubstituted or substituted by 1-3 of substitutes selected from C1-4 alkyl, C1-4 alkoxy, a halogen atom and CFs;

R'is (i) C1-8 alkyl which is unsubstituted or substituted by 1-5 of R™* (ii)

C2-8 alkenyl which is unsubstituted or substituted by 1-5 of R'**, (iii) C2-8 alkynyl which is unsubstituted or substituted by 1-5 of RA (iv) NR*R** (v) OR*A (vi) SH, (vii)

S(O)nR™4, (vii) COR*, (ix) COOR®*, (x) CONR*R**, (xi) NR*COR®** (xii)

® ® NR*COOR®A, (xiii) NR**CONR**R**, (xiv) C3-15 mono- or bi-carbocyclic ring which is unsubstituted or substituted by 1-5 of R'**, (xv) 3-15 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and / or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R'**;

R** is (i) C5-10 mono- or bi-carbocyclic ring substituted by 1-5 of R'®* or (ii) 5-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and / or 1-2 of sulfur(s) substituted by 1-5 of R'*4; was described.

On the other hand, as bi-heterocyclic ring compound, for example, in pamphlet of WO 97/11946, a compound of formula (B): _AB-RSB ) 14B ) Ln (B)

RIB SNS

R128 wherein R''® is a hydrogen, lower alkyl, pyridyl, furyl, thienyl, phenyl which may be substituted by lower alkyl or phenylthio, N-lower alkyl pyrrolyl or pyrazinyl; R'?® is a hydrogen, a halogen atom, phenyl, phenyl which may be substituted by substituents selected by a halogen atom, phenylthio and trifluoromethyl and nitro, or phenyl substituted by lower alkoxy and phenylthio; R™*B is a hydrogen, lower alkyl which may be substituted by oxo, ethylenedioxy, lower alkanoyloxy, lower alkoxy, lower alkylthio, carboxyl, halogen or thienyl, lower alkenyl, cycloalkyl, phenyl, furyl or thienyl which may be substituted by 1-3 of lower alkyl, halogen and lower alkoxy; R'*® is a hydrogen, carboxyl, lower alkoxycarbonyl, nitro, a halogen atom or lower alkyl substituted by lower alkoxy carbonyl or alkali metal salt residue of carboxylic acid; or R"® and R!*® were taken together, may be formed lower alkylene; R!°® is a hydrogen, alkali metal atom, lower alkyl, phenyl which may be substituted by 1-3 of lower alkyl and lower alkoxy, pyridyl, quinolyl or isoquinolyl which may substituted by lower alkyl or halogen; A® is bond or lower alkylene; was described as analgesic drug, in pamphlet of WO 01/32632, a compound of formula (C):

SS

“YT ©

RC —- wherein X' is O or NH; LC is bond or Cl-6 alkylene chain optionally interrupted by O, S, SO, SO; or NH and optionally substituted on alkylene carbon by fluoro, hydroxyl, C1-4 alkoxy or oxo; R'® is unsubstituted or substituted carbocyclic ring

® ® or heterocyclic ring; R* is a hydrogen, a halogen atom, carboxyl, cyano, SCH,CH, or

X*©.R*¢ in which X*€ is bond, O, S, SO, SO, or NH, R*® is C1-8 alkyl, C3-10 cycloalkyl, halo(C1-6) alkyl, hydroxyl(C1-6)alkyl, dihydroxy(C1-6)alkyl, phenyl or phenyl(C1- 4)alkyl in which phenyl is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, C1-4 alkyl and C1-4 alkoxy, etc.; R*® and R* each independently is C1-4 alkyl or together with the carbon atoms to which they are attached form unsubstituted or substituted carbocyclic ring or heterocyclic ring; was described as mGluR1 antagonist.

Disclosure of the Invention

An object of the present invention is to provide an agent which is easily handled and has potent prevention and/or treatment effects in the prevention and/or treatment of psychiatric and neurologic disorders, diseases of peripheral organs or the like.

The present inventors studied intensively in order to solve the above problems, and as a result, found that the object can be achieved by a bicyclic heterocyclic ring.

The present invention relates to the followings: 1. A CREF antagonist comprising, as an active ingredient, a compound represented by formula (I):

R! £ 0) (alia dew

N Zz wherein ring A represents a 5- or 6-membered monocyclic ring which may be substituted with 1 to 3 substituents selected from a halogen atom, CF;, OCFs, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, oxo, and C1-6 alkyl,

C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substituted with 1 10 3 substituents selecied from a halogen atom, CFs and hydioxyl; ring B represents a 5- to 7-membered monocyclic unsaturated heterocyclic ring which may contain 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and/or a sulfur atom which may be oxidized, other than the nitrogen atom, W' and W? and which may be further substituted;

W! and W? each independently, represents a carbon atom or a nitrogen atom;

Z represents -NR’-, in which R® represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be substituted, -CO-(C1-6 alkyl which may be substituted), -SO2-(C1-6 alkyl which may be substituted), an oxygen atom, a sulfur atom which may be oxidized, or -CR*R’-, in which R* and R® each independently represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be substituted,

_ ® or R* and R® may be taken together to represent (i) oxo, (ii) C2-5 alkylene in which one carbon atom may be substituted with one oxygen atom, nitrogen atom or sulfur atom which may be oxidized, wherein the C2-5 alkylene may be substituted with a substituent(s), or (iii) C1-6 alkylidene which may be substituted;

R! represents: 1) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted, (i) amino which may be protected, (11) hydroxyl which may be protected, (iv) mercapto which may be protected, (v) -S(0)aR®, in which n represents 1 or 2, and R® represents (a) C1-15 alkyl, C2- alkenyl or C2-15 alkynyl which each may be substituted or (b) a cyclic group which may be substituted, (vi) -COR’, in which R represents (a) a hydrogen atom, (b) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted, (c) hydroxyl which may be 15 protected, (d) amino which may be protected, or (e) a cyclic group which may be substituted, or (vii) a cyclic group which may be substituted;

R? represents an unsaturated cyclic group which may be substituted, in which the substituent may be taken together with R? to form C2-5 alkylene which may be substituted, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. 2. A compound represented by formula (I-A):

R!

C

L-.C RR?

N z n! ¢ wherein 7) represents a ring selected from (agin)

NT

(1) cyclic group 1:

® ® R! R! R! R!

EY Lr ary ors — N° , — N° , — N° , — i ,

R' R' R' R! 20 7H CY a

N=? ’ NEN ’ = 2 ’ =? ’

R! R' R'

SY se SY

NTN , NT? and NRF and 2) cyclic group 2:

R® R!® R'? a Rr? nN N7 0 N nN = N7

R? R'? R!? R!? R!? so iRes lee CG IReS = N\ My = = No ~ Pp 0 nN , x7 , N= ONT, N V7, NT,

R!? R"™ rR R!* R'?

ENS EN 0 EN =r ) x

N°, ONT NT, NT, OTN

R!? R!? R!? § | = S, - = 0 = —

NE Ny” and NTS and ring A may be substituted with 1 to 3 substituents selected from a halogen atom, CFs, OCF, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, oxo, and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substituted with 1 to 3 substituents selected from a halogen atom, CF; and hydroxyl, and ring B may be further substituted;

R! represents: (1) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted, (i) amino which may be protected, (iif) hydroxy! which may be protected, (iv) mercapto which may be protected,

® ® v) -S(0),R®, in which n represents | or 2, and R® represents (a) C1-15 alkyl, C2- 15 alkenyl or C2-15 alkynyl which each may be substituted, or (b) a cyclic ring which may be substituted, (vi) -COR’, in which R’ represents (a) a hydrogen atom, (b) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted, (c) hydroxy! which may be protected, (d) amino which may be protected, or (e) a cyclic group which may be substitute, or (vin) a cyclic group which may be substituted;

R'® represents: (1) C1-15 alkyl or C2-15 alkenyl which may be substituted with substituent group 1, (i) NR®R’, in which R® represents (a) a hydrogen atom or (b) C1-15 alkyl or

C2-15 alkenyl which each may be substituted with substituent group 1, and R’ represents (a) a hydrogen atom, (b) C1-15 alkyl or C2-15 alkenyl substituted with substituent group 1, (c) -COR' in which R" represents (aa) a hydrogen atom or (bb) C1-15 alkyl or C2-15 alkenyl which each may be substituted with substituent group 1, (d) -COOR', in which

RY has the same meaning as described above, or (e) -CON(R®),, in which R®s each independently has the same meaning as described above, (iii) OR", in which R'° has the same meaning described above, (iv) SR in which R'° has the same meaning described above, v) S(O).R", in which n represents 1 or 2, and R'! represents C1-15 alkyl or C2-15 alkenyl which each may be substituted with substituent group 1, or (vi) COR'?, in which R'? represents (a) a hydrogen atom, (b) C1-15 alkyl or C2-15 alkenyl which each may be substituted with substituent group 1, (c) -OR'®, in which R'° has the same meaning as described above, or (dj -NR®R’, in which R® and R® have the same meanings as described above; the substituent group 1 represents (1) a halogen atom, (2) CFs, (3) OCH, (4) cyano, (5) nitro, (6) hydroxyl, (7) C1-6 alkoxy, (8) carboxyl, (9) (C1-6 alkoxy)carbonyl, (10) C1-5 acyl, (11) carbamoyl in which a nitrogen atom may be protected with 1 or 2 of

Cl-6 alkyl, (12) C1-6 alkylthio, (13) C1-6 alkylsulfonyl, or (14) NR"R'* in which R" represents (a) a hydrogen atom, (b) C1-6 alkyl, or (c) C2-6 alkenyl, and R'* represents (a)a hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) -COR"?, in which R"® represents (aa) a hydrogen atom, (bb) C1-6 alkyl or (cc) C2-6 alkenyl, (¢) -COOR"’, in which R'® has the same meaning as described above, or (f) -CON(R'®),, in which R'®s each independently represents a hydrogen atom or C1-6 alkyl,

Z® represents -NR>-, in which R® represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be substituted, -CO-(C1-6 alkyl which may be

® substituted), -SO;-(C1-6 alkyl which may be substituted), an oxygen atom, a sulfur atom which may be oxidized, or -CR*R’-, in which R* and R® each independently represents a hydrogen atom, or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be substituted, or R* and R® may be taken together to represent (i) oxo, (ii) C2-5 alkylene in which one carbon atom may be substituted with one oxygen atom, nitrogen atom or sulfur atom which may be oxidized, wherein the C2-5 alkylene may be substituted with a substituent(s), or (iii) C1-6 alkylidene which may be substituted;

R* represents (1) a C5-12 monocyclic or bicyclic unsaturated carbocyclic ring which may be substituted, (2) pyridine which may be substituted, (3) a bicyclic heterocyclic ring which may be substituted, in which benzene and a 5- or 6-membered monocyclic heterocyclic ring are fused, (4) a bicyclic heterocyclic ring which may be substituted, in which a pyridine ring and a C5-6 monocyclic carbocyclic ring are fused, or (5) a bicyclic heterocyclic ring which may be substituted, in which a pyridine ring and a 5- or 6-membered monocyclic heterocyclic ring are fused, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. 3. The compound according to the above 2,

R wherein the ring TR is (akin

N

R! rR! R! R!

A A

0 N-NTSN J > JN SN

AJ AJ A) a)

RI? R!® R'? R!? ~ ~N oT Ne

EU = = IW wherein all symbols have the same meanings as described in claim 2, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. 4, The compound according to the above 2, wherein R' is amino which may be protected, or R'is NR®R®, in which R® and R® have the same meanings as described in the above 2, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. 5. The compound according to the above 2, wherein Z* is -NR*-, in which R? has the same meaning as described in the above 2, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

6. The compound according to the above 2, wherein Z* is -CR*®R*-, in which R* and R* are taken together to represent C2-5 alkylene in which one carbon atom may be substituted with one oxygen atom, nitrogen atom or sulfur atom which may be oxidized, wherein the C2-5 alkylene may be substituted with a substituent(s), a salt thereof, an

N-oxide thereof, a solvate thereof or a prodrug thereof. 7. The compound according to the above 2, which is represented by formula (I-A- 3):

RIA

G N

All 2 (I-A-3)

Le

N N

I

RIA

. -C . wherein Ya) 1s 2. -~C

N

RA RIA Gc RA Gc! RIA

G? G? al N-N = al Ney al 74 N ~N al 74 NS

UES FL EE a SG

N N N™°N N™°N

Gc! ’ Gg! 4 or

R'* represents amino which may be protected with 1 or 2 of C1-15 alkyl which may be substituted;

G*'s each independently represents a hydrogen atom, a halogen atom, CF;, OCF;, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, or

C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substituted with 1 or 2 substituents seiected from a halogen atom, Ct; and hydroxyl,

G? represents a hydrogen atom, C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted, hydroxyl which may be protected, cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl, a halogen atom, CFs, or cyano; and other symbols have the same meanings as in the above 2, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. 8. The compound according to the above 2, which is represented by formula (I-A- 4):

® o Rlz-A £ (a) { 5) (I-A-4)

NS

N N

IN

Rla-A wherein ON is pa RA pe RI*A pre RIA RIA

G? ue eT 1 Sy

N N N N™°N

G2 ’ G2 pe or

R'*# represents NR*R*2, in which one of R** and R** represents C1-15 alkyl which may be substituted with the substituent group 1 and another represents a hydrogen atom or C1-15 alkyl which may be substituted with the substituent group 1, wherein the substituent group 1 has the same meaning as in the above 2;

Gs each independently represents a hydrogen atom, a halogen atom, CFs, ~~ OCFs3, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, oxy, oxo, or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substituted with 1 or 2 substituents selected from a halogen atom, CF; and hydroxyl; and other symbols have the same meanings as described in the above 2 or 7, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. : 9. The compound according to the above 2, which is: 4) N° -(2-chloro-4-methoxyphenyl)-6-methyl-N’ N"-dipropylpyrazolo[ 1,5- a]pyrimidine-5,7-diamine, 2) N°-(2-chloro-4-methoxyphenyl)-N-(1 -ethylpropyl)-6-methylpyrazolo[1,5- a]pyrimidine-5,7-diamine, (3) N°-(2-chloro-4-methoxyphenyl)-6-ethyl-N’ N’-dipropylpyrazolo[ 1,5- a]pyrimidine-5,7-diamine, (4) N?-(2-chloro-4-methoxyphenyl)-N-ethyl-N* N*-dipropyl-6, 7-dihydro-5H- cyclopenta[d]pyrimidine-2,4-diamine, 6) N°-(2-chloro-4-methoxyphenyl)-6-methoxy-N’,N’-dipropylpyrazolo[ 1,5- a]pyrimidine-5,7-diamine, (6) NZ-allyl-N?-(2-chloro-4-methoxyphenyl)-N* N*-dipropyl-6,7-dihydro-SH- cyclopenta[d]pyrimidine-2,4-diamine,

® ® ©) 6-methyl-N’-[2-methyl-4-(trifluoromethoxy)phenyl]-N’,N’- dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine, 8) N’-butyl-N’ -(2-chloro-4-methoxyphenyl)-N"-ethyl-6-methylpyrazolo[1,5- a]pyrimidine-5,7-diamine, (9) N° -(2-ethyl-4-methylphenyl)-6-methyl-N’ N’-dipropylpyrazolo[1,5- a]pyrimidine-5,7-diamine, (10) 6-methoxy-N° -(4-methyl-2-vinylphenyl)-N’ N’-dipropylpyrazolo[ 1,5- a]pyrimidine-5,7-diamine, or (11) N° -(2-ethyl-4-methylphenyl)-6-methoxy-N’ N”-dipropylpyrazolo[1,5- a]pyrimidine-5,7-diamine, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof 10. A pharmaceutical composition comprising, as an active ingredient, the compound represented by formula (I-A) according to the above 2, a salt thereof, an

N-oxide thereof, a solvate thereof or a prodrug thereof. 11 The pharmaceutical composition according to the above 10, which is a CRF antagonist. 12. The pharmaceutical composition according to the above 10, which is an agent for preventing and/or treating CRF mediated diseases. 13. The pharmaceutical composition according to the above 12, wherein the CRF mediated diseases are psychiatric and neurologic disorders or digestive diseases. 14. The pharmaceutical composition according to the above 13, wherein the psychiatric and neurologic disorders or the digestive diseases are mood disorders, anxiety disorders, stress-related disorders, eating disorders, symptom caused by psychotropic substance or dependency thereon, organic mental disorder, schizophrenic disorder, attention-deficit hyperactivity disorder or irritable bowel syndrome. 15. The pharmaceutical composition according to the above 14, wherein the psychiatric and neurclogic disorders or the digestive discases arc depression, mood disorders, eating disorders, drug addiction, drug dependency or irritable bowel syndrome. 16. A medicament comprising a combination of the compound represented by formula (I-A) according to the above 2, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof with at least one selected from a tricyclic antidepressant, a tetracyclic antidepressant, a monoamine oxidase inhibitor, a serotonin and noradrenaline reuptake inhibitor, a selective serotonin reuptake inhibitor, a serotonin reuptake inhibitor, a psychoanaleptic, an antianxiety agent, an antipsychotic agent, a mitochondrial benzodiazepine receptor ligand, an NK1 antagonist, a gastrointestinal promotility agent, a 5-HT; antagonist, a 5-HT, agonist, an anticholinergic agent, an antidiarrheal drug a lapactic and an autonomic modulating agent.

17. A method for antagonizing CRF, which comprises administering to a mammal an effective amount of the compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof:

R! 2

Qi 0)

L200 UR

N Zz wherein all symbols have the same meanings as described in the above 1. 18. A method for preventing and/or treating a CRF mediated disease, which comprises administering to a mammal an effective amount of the compound represented by formula (I-A), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof:

R! & .

All 5) (I-A)

Lele Re

N z wherein all symbols have the same meanings as described in the above 2. 19. Use of the compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof for the manufacture of a CRF antagonist:

R!

GR) (alin ic R? ® wherein all symbols have the same meanings as described in the above 1. 20. Use of the compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof for the manufacture of a CRF mediated disease: wl

Ls ~

All 5) (I-A)

L-2C R2

N z: wherein all symbols have the same meanings as described in the above 2. wis 2)

In the present invention, ring | \ B / includes, for example,

Wi ---C

N

® 0 fd £2) fn) 5) a)

NTT, NTT, NT, NF, NTT,

Ca) Ye) $a) $a) Vs)

Cs .C C: .C N. # N. 2C or N. =

N ) N , N ’ N N

In the present invention, the 5- or 6-membered monocyclic ring includes a 5- or 6-membered monocyclic carbocyclic ring or monocyclic heterocyclic ring.

The 5- or 6-membered monocyclic carbocyclic ring includes, for example, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene rings.

The 5- or 6-membered monocyclic heterocyclic ring includes a 5- or 6- membered monocyclic heterocyclic ring containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and/or a sulfur atom which may be oxidized. Examples include pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, + tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, pyrrole, imidazole. triazole. tetrazole. pyrazole. pyridine. pyrazine. pyrimidine. pvridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan, thiadiazole, pyran, thiopyran, oxazine, oxadiazine, thiazine and thiadiazine rings.

In the present invention, the 5- to 7-membered monocyclic unsaturated heterocyclic ring which may contain 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and/or a sulfur atom which may be oxidized, other than the nitrogen atom,

W! and W? and which may be further substituted includes a 5- to 7-membered monocyclic unsaturated heterocyclic ring which may be substituted with 1 or 2 substituents selected from the substituent group 2, always contains one nitrogen atom and may contain 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and/or a sulfur atom which may be oxidized, other than the nitrogen atom, W! and W2. Examples include pyrrole,

® ® imidazole, triazole, pyridine, pyrimidine, pyridazine, triazine, azepine, diazepine, oxazine, oxadiazine, oxazepine, oxadiazepine, thiazine, thiadiazine, thiazepine, and thiadiazepine rings.

In this connection, in ring A and ring B, the total number of the nitrogen atoms contained is 5 or less, and the total number of the oxygen atom and the sulfur atom which may be oxidized contained in ring A and ring B is 2 or less.

In the present invention, the substituent group 2 includes: 1) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted, (1) amino which may be protected, (in) hydroxyl which may be protected, (iv) mercapto which may be protected, v) -S(0)aR®, in which n and R® have the same meanings as described above, (vi) -COR’, in which R” has the same meaning as described above, (vii) a cyclic group which may be substituted, and (viii) a halogen atom, CF3, OCFs;, nitro, or cyano.

In the present invention, the sulfur atom which may be oxidized includes S, SO, and SO.

In the present invention, the C1-15 alkyl which may be substituted includes straight or branched C1-15 alkyl which may be substituted, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl, which each may be substituted.

In the present invention, the C2-15 alkenyl which may be substituted includes straight or branched C2-15 alkenyl having 1 to 3 double bonds which may be substituted, and examples include vinyl, propenyl, butenyl, pentenyl, hexenyl, hexadienyl, heptenyl, heptadienyl, octenyl, octadienyl, nonenyl, nonadienyl, decenyl, decadienyl, undecenyl, dedecenyl, tridecenyl, tetradecenyl and pentadecenyl which each may be substituted,

In the present invention, the C2-15 alkynyl which may be substituted includes straight or branched C2-15 alkynyl having 1 to 3 triple bonds which may be substituted, and examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, hexadiynyl, heptynyl, heptadiynyl, octynyl, octadiynyl, nonyl, decynyl, undecynyl, dodecynyl, tridecynyl, : tetradecynyl and pentadecynyl, which each may be substituted.

In the present invention, the substituent group 1 in "C1-15 alkyl or C2-15 alkenyl which may be substituted with substituent group 1" may be substituted on 1 to 4 substitutable positions on the C1-15 alkyl or C2-15 alkenyl.

The substituent group 1 includes (1) a halogen atom, (2) CFs, (3) OCF;, (4) cyano, (5) nitro, (6) hydroxyl, (7) C1-6 alkoxy, (8) carboxyl, (9) (C1-6 alkoxy)carbonyl,

® ® (10) C1-5 acyl, (11) carbamoyl in which a nitrogen atom may be protected with 1 or 2 of

C1-6 alkyl, (12) C1-6 alkylthio, (13) C1-6 alkylsulfonyl, and (14) NR*R'* in which R"? is (a) a hydrogen atom, (b) C1-6 alkyl, or (c) C2-6 alkenyl, and R'* represents (a) a hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) -COR', in which R'* represents (aa) a hydrogen atom, (bb) C1-6 alkyl or (cc) C2-6 alkenyl, (e) ~-COOR'’, in which R! has the same meaning described above, or (f) -CON(R'®),, in which R's each independently represents a hydrogen atom or C1-6 alkyl.

In the present invention, the C1-6 alkyl which may be substituted includes straight or branched C1-6 alkyl which may be substituted, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, fert-butyl, pentyl and hexyl, which each may be substituted.

In the present invention, the C2-6 alkenyl which may be substituted includes straight or branched C2-6 alkenyl having one double bond which may be substituted, and examples include vinyl, propenyl, butenyl, pentenyl and hexenyl, which each may be substituted.

In the present invention, the C2-6 alkynyl which may be substituted includes straight or branched C2-6 alkynyl having one triple bond which may be substituted, and examples include ethynyl, propynyl, butynyl, pentynyl and hexynyl, which each may be substituted.

In the present invention, the C2-5 alkylene or the C2-5 alkylene which may be substituted includes methylene, methylene, ethylene, trimethylene, tetramethylene, pentamethylene and isomers thereof.

In the present invention, the C1-6 alkylidene which may be substituted includes methylidene, ethylidene, propylidene, pentylidene, hexylidene and isomers thereof,

In the present invention, the "C1-6 alkyl which may be substituted", the "C2-6 alkenyl which may be substituted", the "C2-6 alkynyl which may be substituted", the "C2- 5 aixyicnc which may be substituted”, the "C1-6 alkylidenc which may be substituted", the “C1-15 alkyl which may be substituted", the "C2-15 alkenyl which may be substituted", the "C2-15 alkynyl which may be substituted" and the "C1-15 alkoxy which may be substituted" include "substituted or unsubstituted C1-6 alkyl", "substituted or unsubstituted

C2-6 alkenyl”, "substituted or unsubstituted C2-6 alkynyl", "substituted or unsubstituted

C2-5 alkylene", "substituted or unsubstituted C1-6 alkylidene", "substituted or unsubstituted C1-15 alkyl", "substituted or unsubstituted C2-15 alkenyl", "substituted or unsubstituted C2-15 alkynyl" and "substituted or unsubstituted C1-15 alkoxy", and the "substituent(s)" include the following substituent group 3.

The substituent group 3 includes (1) a halogen atom, (2) CFs, (3) OCF;, (4) cyano, (5) nitro, (6) hydroxy! which may be protected with C1-6 alkyl, C2-6 alkenyl, C2-6

® alkynyl, a cyclic group or a protective group having leaving ability, (7) C1-7 acyl, (8) carbonyl which may be protected with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or a cyclic group, (9) carbamoyl which may be protected with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or a cyclic group, (10) thiol which may be protected with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or a cyclic group, (11) NR'R"®, in which R"’ represents (a) a hydrogen atom, (b)

C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, or (e) a cyclic group; and R'® represents (a) a hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) -COR?, in which

R? represents (aa) a hydrogen atom, (bb) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl or (cc) a cyclic group, (f) -COOR?, in which R has the same meaning as described above, or (g) -CON(R'), in which R's each independently has the same meaning as described above, (12) -S(0),R", in which n has the same meaning as described above, and R' represents (a) a hydrogen atom, (b) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl or (c) a cyclic group, (13) -COR®, in which R™ has the same meaning as described above, and (14) a cyclic group which may be substituted. These substituents may be substituted on 1 to 4 16 substitutable positions. Furthermore, the C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl in the substituent group 3 may be substituted with a substituent(s) selected from the substituent group 5, and the cyclic group may be substituted with a substituent(s) selected from the substituent group 4.

In the present invention, the halogen atom includes fluorine, chlorine, bromine and iodine.

In the present invention, C1-6 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

In the present invention, C2-6 alkenyl includes, for example, vinyl, propenyl, butenyl, pentenyl, hexenyl and hexadienyl.

In the present invention, C2-6 alkynyl includes, for example, ethynyl, propynyl, = butynyl, pentynyl, hexynyl and hexadiynyl.

Lil the pieseit iiiveinion, tie hydroxyl wiidh may be proiccicd wiilt Ci-6 aikyi includes C1-6 alkoxy.

In the present invention, the C1-6 alkoxy includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, fert-butoxy, pentyloxy and hexyloxy.

In the present invention, the C1-15 alkoxy includes, for example, straight or branched C1-15 alkoxy, and examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, fert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy and pentadecyloxy.

In the present invention, the C1-6 alkylthio includes, for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, zert-butylthio, pentylthio and hexylthio.

In the present invention, the C1-5 acyl includes, for example, formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl and pivaloy!.

In the present invention, the C1-7 acyl includes, for example, formyl, acetyl, propanoyl, pivaloyl and benzoyl.

In the present invention, the (C1-6 alkoxy)carbonyl includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, fert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.

In the present invention, the carbamoyl in which a nitrogen atom may be protected with 1 or 2 of C1-6 alkyl includes N-(C1-6 alkyl)carbamoyl and N,N-di(C1-6 alkyl)carbamoyl.

In the present invention, the amino which may be protected includes amino protected with 1 or 2 of the following protecting groups, and unsubstituted amino. The amino-protecting groups include (a) C1-15 alkyl which may be substituted, (b) C2-15 alkenyl which may be substituted, (c) C2-15 alkynyl which may be substituted, (d) a cyclic group which may be substituted, (e) -COR?', in which R*! represents (aa) a hydrogen atom, (bb) CI-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted or (cc) a cyclic group which may be substituted, (f) -COOR?', in which R* has the same meaning as described above, and (g) -CON(R*?),, in which R*s each independently represents (aa) a hydrogen atom or (bb) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted.

In the present invention, hydroxyl! which each may be protected includes, for example, (a) C1-15 alkyl which may be substituted, (b) C2-15 alkenyl which may be substituted, (c) 7-15 alkynyl which may he substituted, (d) a cvelic group which mav be substituted, and (e) hydroxyl or hydroxyl protected with a protecting group having leaving ability. Herein, the protecting group having leaving ability includes, for example, trityl, methoxymethyl (MOM), 1l-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsily (TBDMS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc) and 2,2,2-trichloroethoxycarbony! (Troc).

Also, the hydroxyl protected with C1-15 alkyl which may be substituted includes C1-15 alkoxy which may be substituted.

In the present invention, the mercapto which may be protected includes mercapto protected with (a) C1-15 alkyl which may be substituted, (b) C2-15 alkenyl

® ® which may be substituted, (c) C2-15 alkynyl which may be substituted or (d) a cyclic group which may be substituted, and unsubstituted mercapto.

In the present invention, the cyclic group includes a carbocyclic group and a heterocyclic group. The carbocyclic group includes a C3-12 monocyclic or bicyclic carbocyclic group, and examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, heptalene, perhydroheptalene and bicyclo[3.1.1]heptane ring groups.

The heterocyclic group includes a C3-12 monocyclic or bicyclic heterocyclic ring containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and/or a sulfur atom which may be oxidized, and examples include oxirane, thiirane, aziridine, oxetane, thietane, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (tsothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahudroovazine, dihvdroovadiazine, tetrahvdroovadiazine, dihydrooxazenine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, . perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,

® ® tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,

Dbenzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzooxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzoxepine, benzoxazepine, benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine, benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole and benzotriazole ring groups.

In the present invention, the cyclic group which may be substituted includes a carbocyclic group and a heterocyclic group, which each may be substituted with the substituent group 4. The carbocyclic group and the heterocyclic group include those groups described above.

The substituent group 4 includes (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C2-6 alkynyl, (4) hydroxyl which may be protected with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, a cyclic group or a protecting group having leaving ability, (5) mercapto which may be protected with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or a cyclic group, (6) amino which may be protected with 1 or 2 groups selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and a cyclic group, (7) carbamoyl which may be protected with 1 or 2 groups selected from Cl1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and a cyclic group, (8) sulfamoyl which may be protected with 1 or 2 groups selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and a cyclic group, (9) carboxyl which may be protected with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or a cyclic group, (10) nitro, (11) cyano, (12) amidino, (13) a halogen atom, (14)

CFs, (15) OCF;, (16) C1-7 acyl, (17) oxo, and (18) thioxo. These substituents may be substituted on 1 to 5 substitutable positions. Furthermore, in the substituent group 4, the

C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl may be substituted with a substituent(s)

* selected from the substituent group 5, and the cyclic group may be substituted with a substituent(s) selected from the substituent group 6.

The substituent group 5 includes (1) C1-6 alkoxy, (2) C1-6 alkylthio, (3) a halogen atom, (4) hydroxyl which may be protected with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, a cyclic group, cyclic group-C1-6 alkyl or a protecting group having leaving ability, (5) CFs, (6) OCFs, (7) nitro, (8) cyano, (9) carboxyl, (10) (C1-6 alkoxy)carbonyl, (11) benzyloxycarbonyl, (12) mercapto, (13) amino, (14) C1-6 alkylamino, (15) di(C1-6 alkyl)amino, (16) carbamoyl, (17) N-(C1-6 alkyl)carbamoyl, (18) N,N-di(C1-6 alkyl)carbamoyl, (19) sulfamoyl, (20) N-(Cl-6 alkyl)suifamoyl, (21) N-di(C1-6 alkyl)sulfamoyl, (22) C1-7 acyl, and (23) a cyclic group which may be substituted with the substituent group 6.

The substituent group 6 includes (1) C1-6 alkyl, (2) C2-6 alkenyl, 3) C2-6 alkynyl, (4) C1-6 alkoxy, (5) C1-6 alkylthio, (6) a halogen atom, (7) CFs, (8) OCF;, (9) nitro, (10) cyano, (11) hydroxyl which may be protected which may be protected with C1- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, a cyclic group, cyclic group-C1-6 alkyl or a protecting group having leaving ability, (12) carboxyl, (13) (C1-6 alkoxy)carbonyl, (14) benzyloxycarbonyl, (15) mercapto, (16) amino, (17) C1-6 alkylamino, (18) di(C1-6 alkyl)amino, (19) carbamoyl, (20) N-(C1-6 alkyl)carbamoyl, (21) N,N-di(C1-6 alkyl)carbamoyl, (22) sulfamoyl, (23) N-(C1-6 alkyl)sulfamoyl, (24) N-di(C1-6 alkyl)sulfamoyl, (25) C1-7 acyl, (26) oxo, and (27) thioxo.

In the present invention, the cyclic group-C1-6 alkyl includes carbocyclic group-C1-6 alkyl and heterocyclic group-C1-6 alkyl, such as C1-6 alkyl! substituted with one carbocyclic group and C1-6 alkyl substituted with one heterocyclic group, respectively.

The carbocyclic group, the heterocyclic group and the C1-6 alkyl have the same meanings as described above. © 7 oo

In the present invention, the unsaturated cyclic group which may be substituted includes an unsaturated carbocyclic group and an unsaturated heterocyclic group, which each may be substituted with 1 to 5 substituents selected from the substituent group 7.

The unsaturated carbocyclic group includes a C5-12 monocyclic or bicyclic unsaturated carbocyclic group, and examples include benzene, pentalene, indene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene and azulene ring groups. In this connection, in the case of the indene, indane, dihydronaphthalene and tetrahydronaphthalene ring groups, the benzene ring in these ring groups is bound to the group Z.

The unsaturated heterocyclic group includes a 5- to 12-membered monocyclic or bicyclic unsaturated heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and/or a sulfur atom which may be oxidized. Examples

® ® include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnoline, naphthyridine, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole ring groups. In this connection, in the case of the indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, phthalazine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole and benzotriazole ring groups, the benzene ring in these ring groups is bound to the group Z.

The substituent group 7 includes (1) C1-15 alkyl which may be substituted, (2)

C2-15 alkenyl which may be substituted, (3) C2-15 alkynyl which may be substituted, (4) hydroxyl which may be protected, (5) mercapto which may be protected, (6) amino which may be protected, (7) carbamoyl which may be protected, (8) sulfamoyl which may be protected, (9) carboxyl which may be protected, (10) sulfo which may be protected (-SOsH), (11) sulfino which may be protected (-SO.H), (12) nitro, (13) cyano, (14) amidino, (15) imino, (16) a halogen atom, (17) a cyclic group which may be substituted, (18) C1-7 acyl, (19) oxo, (20) thioxo and (21) sulfino which may be protected (-SOH).

These substituents may be substituted on 1 to 5 substitutable positions.

In the present invention, the "protecting group" in the "carbamoyl which may be protected”, the "sulfamoyl which may be protected”, the "carboxyl which may be protected", the "sulfo which may be protected", the "sulfino which may be protected" and the "sulfino which may be protected” includes (a) C1-15 alkyl which may be substituted, (b) C2-15 alkenyl which may be substituted, (c) C2-15 alkynyl which may be substituted, and (d) a cyclic group which may be substituted.

In the present invention, the C5-12 monocyclic or bicyclic unsaturated carbocyclic ring which may be substituted includes a C5-12 monocyclic or bicyclic unsaturated carbocyclic ring which may be substituted with 1 to S substituents selected from the above substituent group 7, and examples include benzene, pentalene, indene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene and azulene rings. In this connection, in the case of the indene, indane, dihydronaphthalene and tetrahydronaphthalene rings, the benzene ring in these rings is bound to Z2,

In the present invention, the substituent in the pyridine which may be substituted includes 1 to 4 substituents selected from the above substituent group 7.

® In the present invention, the bicyclic heterocyclic ring which may be substituted, in which benzene and a 5- or 6-membered monocyclic heterocyclic ring, includes a bicyclic heterocyclic ring which may be substituted with 1 to 5 substituents selected from the above substituent group 7, in which benzene and a 5- or 6-membered monocyclic heterocyclic ring are fused, and examples include indole, isoindole, indoline, isoindoline, benzofuran, isobenzofuran, dihydrobenzofuran, dihydroisobenzofuran, benzothiophene, isobenzothiophene, dihydrobenzothiophene, dihydroisobenzothiophene, chroman and isochroman rings, in which the benzene ring in these rings is bound to the group Z°.

In the present invention, the bicyclic heterocyclic ring which may be substituted, in which a pyridine ring and C5-6 monocyclic carbocyclic ring are fused, include a bicyclic heterocyclic ring which may be substituted 1 to 5 substituents selected from the above substituent group 7, in which a pyridine ring and a C5-6 monocyclic carbocyclic ring are fused, and examples include quinoline, isoquinoline, tetrahydroquinoline and tetrahydroisoquinoline rings. In the case of the tetrahydroquinoline and tetrahydroisoquinoline rings, the pyridine ring binds to the group

VA

In the present invention, the bicyclic heterocyclic ring which may be substituted, in which a pyridine ring and a 5- or 6-membered monocyclic heterocyclic ring are fused, includes a bicyclic heterocyclic group which may be substituted with 1 to S substituents selected from the substituent group 7, in which a pyridine ring and a 5- or 6- membered monocyclic heterocyclic ring are fused, and examples include naphthyridine.

In the present invention, the C3-6 cycloalkyl which may contain 1 or 2 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran, aziridine, azetidine, pyrrolidine, piperidine, morpholine and thiomorpholine.

In the present invention, preferred rings as ring A are cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pyrroline, pyrrolidine, pyrrole, imidazoline, imidazolidine, imidazole, pyrazole, triazoline, triazolidine, triazole, tetrazoline, tetrazolidine, tetrazole, dihydrofuran, tetrahydrofuran, furan, dihydrothiophene, tetrahydrothiophene, thiophene, dihydrofurazan, tetrahydrofurazan, furazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine) and thiadiazole. Particularly, cyclopentane, cyclopentene, pyrrole, imidazole, pyrazole, triazole, tetrahydrofuran, furan, furazan and thiadiazole are preferred.

_ ® In the present invention, ring A is preferably unsubstituted or substituted with 1 or 2 substituents selected from a halogen atom, CFs, OCF;, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, oxo, and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or Cl-6 alkylthio which each may be substituted with 1 or 2 substituents selected from a halogen atom, CF; and hydroxyl. Ring A is more preferably unsubstituted ring A, or ring A substituted with 1 or 2 substituents selected from a halogen atom, CF3, hydroxyl, carboxyl, (C1-6 alkoxy)carbonyl, cyano, oxo, and C1-6 alkyl or C1-6 alkoxy which each may be substituted with 1 or 2 substituents selected from a halogen . atom, CF; and hydroxyl.

In the present invention, preferred rings as ring B are pyrrole, imidazole, pyridine, pyrimidine, pyridazine, triazine, azepine, diazepine, oxazine, oxazepine, thiazine and thiazepine. Particularly preferred are pyridine, pyrimidine, pyridazine and triazine.

In the present invention, ring B is preferably a ring having no substituent other than R' and -Z-R?, or a ring further substituted with 1 or 2 substituents selected from the above substituent group 2. Ring B is more preferably ring B having no further substituent, or ring B further substituted with 1 or 2 substituents selected from C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted, hydroxyl which may be protected, cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl, a halogen atom, CF; and cyano in the above substituent group 2. Ring B is most preferably ring B having no further substituent or ring B further substituted with one substituent selected from C1-6 alkyl or C2-6 alkenyl which each may be substituted, hydroxyl which may be protected with C1-6 alkyl which may be substituted, cyclopropane, cyclobutane, a halogen atom, CF; and cyano. In this connection, the substituent of the C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl is preferably one substituent selected from C1-6 alkoxy, a halogen atom, hydroxyl,

CN and COOH. ”

In the present invention, Z or Z* is preferably -NR>-, in which R® has the same meaning as described above, an oxygen atom, a sulfur atom which may be oxidized, -CR*R>*-, in which R* and R** are taken together to represent (i) oxo, (ii) C2-5 alkylene in which one carbon atom may be substituted with one oxygen atom, nitrogen atom or sulfur atom which may be oxidized, the C2-5 alkylene being substituted with a substituent(s), or (iit) C1-6 alkylidene which may be substituted. Z or Z* is preferably -NR’-, in which R® has the same meaning as described above, or -CR®R*®-_ in which R* and R* are taken together to represent C2-5 alkylene in which one carbon atom may be substituted with one oxygen atom, nitrogen atom or sulfur atom which may be oxidized, the C2-5 alkylene being substituted with a substituent(s), and most preferably -NR’-, in which R® has the same meaning as described above. Among

® 0 these, -NR*- in which R* is a hydrogen atom, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl or substituted C2-6 alkenyl, is particularly preferred.

In the present invention, when the ring represented by R? and R* is a bicyclic unsaturated carbocyclic ring or bicyclic unsaturated heterocyclic ring containing benzene or a pyridine ring, the benzene or the pyridine ring is bound to the group Z or Z°.

In the present invention, preferred compounds represented by formula (I) are those exemplified in the following Tables.

Table 1

I

Alig) (1-B-1) (afiz) _R?

N N

R® 16 1-C oy 0) 4 _ 12 »

CL \

N-NXN EN 2 a 13 II)

N N o

NX SN

3 0) 14 CI)

N N os 0 4 ll 15 P ans s}

A 16 $0) se WL

EN N x ke

Zl 17 Oo _| _ 6 NF? NTN 7 0) 13 ac) =A Nn?

NTN SN

3 NL 19 LX) =A NZ se SW 4 9 =p 20 0?

SD 21 SIN = N= nN?

Ny =N 11 py N

NE

® Table 2

R!

AllB (I-B-1)

NAN

R3 oy <= is n ~.~C ~~. C

N N

— = AN 22 33 O_I

N= N » 23 CD 34 O"™N == 0 NEN 24 oC) 35 lp

N= N 25 1 \ 36 =r °N - N

S

N O™™N

SA ON

2 | SY 3s CL \ N

S O a | ery EN»

NSN” NN

Sx 0 NPE » | CY LE EES

NTN (AN Co

No 0 | CT a

SS N_~

Ney: ° | aT

SN? NSN? 2 CT)

SN”

In the present invention, more preferred compounds are compounds of formula d-A).

In the present invention, preferred compounds represented by formula (I-A) are those exemplified in the following Tables and following Example compounds.

Table 3 R! ) . , (I-A-1)

NN

Re 1°83

No. (lis) ~v-

N.

NX

1 0)

N

Nyx

NN

2 Eg

N

EN

; 0)

N

~~ 4 CL)

N

J 1)

IN

NN

NN

6 a

Nl

MY

7 N =

NTN

8 N — ~~ —L

NEVE

9 ¢ Dp

NZ?

@® .

Table 4 X 1-C 7) (-A-2) “nn R ‘3

R

C3 C2

No. Q 2) No. Qn 20) ~N-C ~N-C .® CIC) 1 z 10 7

N NT

A ~N 2 oI) oI

N 11 ND 0 ow: 3 P 2 Pp

N I (0) Nn xX o ~N 4 C1) 13 CO

O™™N N ~= ~~ =~ ~N : CL) 14 oJ

N N

6 QC) 15 71)

N O™™N ~ Oo >

O™™N N

Nx No

LJ 17 sol)

N™>N NTN

N N

NTN NSN

In Tables 1 to 4, ring A is preferably unsubstituted or substituted with 1 or 2 substituents selected from a halogen atom, CF3, OCF, hydroxyl, mercapto, carboxyl, (C1- 6 alkoxy)carbonyl, carbamoyl, nitro, cyano, oxo, and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substituted with 1 or 2 substituents selected from a halogen atom, CF; and hydroxyl. Ring A is more preferably unsubstituted ring A, or ring A substituted with 1 or 2 substituents selected from a halogen atom, CF3, hydroxyl, carboxyl, (C1-6 alkoxy)carbonyl, cyano, oxo, and C1-6 alkyl or C1-6

@® ® alkoxy which each may be substituted with 1 or 2 substituents selected from a halogen atom, CF; and hydroxyl.

In Tables 1 to 4, each ring represented by ring B may be substituted with 1 or 2 substituents selected from the above substituent group 2 on substitutable position(s).

Among the substituent group 2, C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted, hydroxyl which may be protected, cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl, a halogen atom, CF; and cyano are preferred. Ring B is more preferably unsubstituted ring B, or ring B substituted with one substituent selected from C1-6 alkyl or C2-6 alkenyl which each may be substituted, hydroxyl which may be protected with C1-6 alkyl which may be substituted, cyclopropane, cyclobutane, a halogen atom, CF; and cyano.

R! is preferably (i) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted, (ii) amino which may be protected, (iii) hydroxyl which may be protected, (iv) mercapto which may be protected, or (v) a cyclic group which may be substituted. When R'is a cyclic group which may be substituted and the cyclic group is a heterocyclic ring containing a nitrogen atom, the nitrogen atom is preferably bound to ring

B.

In the present invention, R! is more preferably amino which may be protected.

The amino which may be protected is preferably amino which may be protected with 1 or 2 of CI-15 alkyl which may be substituted, and more preferably amino substituted with one

C1-15 branched or straight alkyl which may be substituted, or amino substituted with two

C1-15 branched or straight alkyls which may be substituted. The C1-15 branched or straight alkyl which may be substituted is preferably unsubstituted C1-15 branched or straight alkyl, or C1-15 branched or straight alkyl substituted with 1 or 2 substituents selected from a halogen atom, CF3, cyano, hydroxyl, C1-6 alkoxy, and C3-6 cycloalkyl which may contain 1 or 2 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.

R'® is preferably (i) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted with the above substituent group 1, (ii) NR®R®, in which R® and R® have the same meanings as described above, (iii) OR', in which R' has the same meaning as described above. R'* is more preferably NR®*R®, in which R® and R® are each preferably (a) a hydrogen atom, or (b) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted with the above substituent group 1.

NR®R’ is preferably NR®*R®*, in which one of R®* and R** is C1-15 alkyl which may be substituted with the substituent group 1, and another is a hydrogen atom or

C1-15 alkyl which may be substituted with the above substituent group 1. More specifically, in NR**R®* | preferred are (1) a combination in which R* is a hydrogen atom,

eo and R’ is C1-15 branched or straight alkyl which may be substituted with the above substituent group 1, and (2) a combination in which R® and R>* are each C1-15 branched or straight alkyl which may be substituted with the above substituent group 1. The C1-15 branched or straight alkyl which may be substituted with the above substituent group 1 is preferably unsubstituted C1-15 branched or straight alkyl, or C1-15 branched or straight alkyl substituted with 1 or 2 substituents selected from a halogen atom, CFs, cyano, hydroxyl and C1-6 alkoxy.

R? is preferably a monocyclic or bicyclic unsaturated carbocyclic ring which may be substituted, or a monocyclic or bicyclic unsaturated heterocyclic ring which may be substituted. R? is more preferably a ring represented by R?, that is, (1) a monocyclic or bicyclic unsaturated carbocyclic ring which may be substituted, (2) pyridine which may be substituted, (3) a bicyclic heterocyclic ring which may be substituted, in which benzene and a 5- or 6-membered monocyclic heterocyclic ring are fused, (4) a bicyclic heterocyclic ring which may be substituted, in which a pyridine ring and a C5-6 monocyclic carbocyclic ring are fused, or (5) a bicyclic heterocyclic ring which may be substituted, in which a pyridine ring and a 5- or 6-membered monocyclic heterocyclic ring are fused. R* is preferably a benzene, indene, indane, naphthalene, tetrahydronaphthalene, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, pyridine or naphthyridine ring, which may be substituted, and more preferably a benzene, naphthalene, tetrahydronaphthalene or pyridine ring, which may be substituted. In this connection, in the case of the indene, indane and tetrahydronaphthalene rings, the benzene ring in these rings is bound to Z or Z*,

Also, the “substituent” substituted on the ring represented by R* and R® is preferably a substituent shown in the above substituent group 7. The substituent is preferably (1) C1-15 alkyl which may be substituted, (2) Ci-15 alkenyl which may be substituted, (3) hydroxyl which may be protected, (4) mercapto which may be protected, (5) amino which may be protected, (6) carbamoyl which may be protected, (7) carboxyl which may be protected, (8) sulfo which may be protected, (9) sulfino which may be protected, (10) cyano, (11) a halogen atom, (12) a cyclic group which may be substituted, or (13) sulfino which may be protected. The substituent is more preferably (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) unsubstituted hydroxyl, or hydroxy! protected with C1-6 alkyl which may be substituted or a protecting group having leaving ability (among these, particularly

C1-6 alkoxy and trifluoromethoxy being preferred), (4) carboxyl, or carboxyl protected with C1-6 alkyl or benzyl, (5) cyano, (6) a halogen atom, or (7) a cyclic group which may be substituted. These substituents may be substituted on 1 to 5 substitutable positions on the ring represented by R* and R*, and 1, 2 or 3 substitution is particularly preferred.

Particularly, when R* and R? are a 6-membered monocyclic ring, specifically benzene or a

Claims (25)

®e CLAIMS

1. A CRF antagonist comprising, as an active ingredient, a compound represented by formula (I): R! ¢ 2) Qu SZ N Zz wherein ring A represents a 5- or 6-membered monocyclic ring which may be substituted with 1 to 3 substituents selected from a halogen atom, CF;, OCF3, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, oxo, and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substituted with 1 to 3 substituents selected from a halogen atom, CF; and hydroxyl; ring B represents a 5- to 7-membered monocyclic unsaturated heterocyclic ring which may contain 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and/or a sulfur atom which may be oxidized, other than the nitrogen atom, W' and W? and which may be further substituted, W!' and W? each independently represents a carbon atom or a nitrogen atom; Z represents -NR’-, in which R® represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be substituted, -CO-(C1-6 alkyl which may be substituted), -SO,-(C1-6 alkyl which may be substituted), an oxygen atom, a sulfur atom which may be oxidized, or -CR*R’-, in which R* and R® each independently represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be substituted, or R* and R® may be taken together to represent (i) oxo, (ii) C2-5 alkylene in which one carbon atom may be substituted with one oxygen atom, nitrogen atom or sulfur atom which may be oxidized, wherein the C2-5 alkylene may be substituted with a substituent(s), or (iit) C1-6 alkylidene which may be substituted; R! represents: 6) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted, (i) amino which may be protected, (iit) hydroxyl which may be protected, (iv) mercapto which may be protected, wv) -S(0)aR®, in which n represents 1 or 2, and R® represents (a) C1-15 alkyl, C2- alkenyl or C2-15 alkynyl which each may be substituted or (b) a cyclic group which may be substituted, (vi) -COR’, in which R” represents (a) a hydrogen atom, (b) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted, (c) hydroxyl which may be protected, (d) amino which may be protected, or (¢) a cyclic group which may be substituted, or (vii) a cyclic group which may be substituted; R? represents an unsaturated cyclic group which may be substituted, in which the substituent may be taken together with R’ to form C2-5 alkylene which may be substituted, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

2. A compound represented by formula (I-A): R! 6 All 5) (I-A) L-2C RR? NT Tz R! ¢ wherein a) represents a ring selected from ~x- 1) cyclic group 1: R! R' R' R! =>NT “7 =>NT = R' R' R! R' ne, CY NTN nd GAS NL R' Rr! R' SY "eo SY Noy? , NEN? and NN? and 2) cyclic group 2:

® ® Rr? R!® R!? rR rR” a3 I2 GL Cy Se > =) on? L A= N, R!? R!? Rr? R!? R!? o N \ nN , NZ N N= 7, nN", Rl? Rl2 R'2 R!® R12 NT, O° °NT , NT, No, 0” NT, Ri2 RI? R!? UN s. _| o | _ NT N“>N7 and N"°N and ring A may be substituted with 1 to 3 substituents selected from a halogen atom, CF3;, OCF, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, oxo, and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substituted with 1 to 3 substituents selected from a halogen atom, CF; and hydroxyl, and ring B may be further substituted; R! represents: (1) C1-15 alkyl, C2-15 alkeny! or C2-15 alkynyl which each may be substituted, (i) amino which may be protected, (iii) hydroxyl which may be protected,

(1). mercapto which may be protected, v) -S(0)aR®, in which n represents 1 or 2, and R® represents (a) C1-15 alkyl, C2- alkenyl or C2-15 alkynyl which each may be substituted, or (b) a cyclic ring which may be substituted, (vi) -COR’, in which R” represents (a) a hydrogen atom, (b) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted, (c) hydroxyl which may be protected, (d) amino which may be protected, or (e) a cyclic group which may be substitute, or (vii) a cyclic group which may be substituted; R'® represents: )] Cl1-15 alkyl or C2-15 alkenyl which may be substituted with substituent group 1, (ii) NR®R’, in which R® represents (a) a hydrogen atom or (b) C1-15 alkyl or C2- 15 alkenyl which each may be substituted with substituent group 1, and R® represents (a) a

®

® hydrogen atom, (b) C1-15 alkyl or C2-15 alkenyl substituted with substituent group 1, (c) -COR", in which R!® represents (aa) a hydrogen atom or (bb) C1-15 alkyl or C2-15 alkenyl which each may be substituted with substituent group 1, (d) -COOR', in which R' has the same meaning as described above, or (e) -CON(R®),, in which R% each independently has the same meaning as described above, (iii) OR", in which R'® has the same meaning described above, (iv) SR'® in which R'® has the same meaning described above, wv) S(O).R"!, in which n represents 1 or 2, and R"' represents C1-15 alkyl or C2-15 alkenyl which each may be substituted with substituent group 1, or (vi) COR'?, in which R'? represents (a) a hydrogen atom, (b) C1-15 alkyl or C2-15 alkenyl which each may be substituted with substituent group 1, (c) -OR', in which R' has the same meaning as described above, or (d) -NR®R’, in which R® and R® have the same meanings as described above;

the substituent group 1 represents (1) a halogen atom, (2) CF;, (3) OCF;, (4) cyano, (5) nitro, (6) hydroxyl, (7) C1-6 alkoxy, (8) carboxyl, (9) (C1-6 alkoxy)carbonyl, (10) C1-5 acyl, (11) carbamoyl! in which a nitrogen atom may be protected with 1 or 2 of C1-6 alkyl, (12) C1-6 alkylthio, (13) C1-6 alkylsulfonyl, or (14) NR"R", in which R" represents (a) a hydrogen atom, (b) C1-6 alkyl, or (c) C2-6 alkenyl, and R'* represents (a) a hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) -COR'®, in which R'’ represents (aa) a hydrogen atom, (bb) C1-6 alkyl or (cc) C2-6 alkenyl, (e) -COOR", in which R'* has the same meaning as described above, or (f) -CON(R'®),, in which R's each independently represents a hydrogen atom or C1-6 alkyl,

Z* represents -NR’-, in which R? represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be substituted, -CO-(C1-6 alkyl which may be substituted), -SO,-(C1-6 alkyl which may be substituted), an oxygen atom, a sulfur atom which may be oxidized, or -CR*R’-, in which R* and R’ each independently represents a hydrogen atom, or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be substituted, or R* and R® may be taken together to represent (i) oxo, (ii) C2-5 alkylene in which one carbon atom may be substituted with one oxygen atom, nitrogen atom or sulfur atom which may be oxidized, wherein the C2-5 alkylene may be substituted with a substituent(s), or (iii) C1-6 alkylidene which may be substituted,

R** represents (1) a C5-12 monocyclic or bicyclic unsaturated carbocyclic ring which may be substituted, (2) pyridine which may be substituted, (3) a bicyclic heterocyclic ring which may be substituted, in which benzene and a 5- or 6-membered monocyclic heterocyclic ring are fused, (4) a bicyclic heterocyclic ring which may be substituted, in which a pyridine ring and a C5-6 monocyclic carbocyclic ring are fused, or

(5) a bicyclic heterocyclic ring which may be substituted, in which a pyridine ring and a 5- or 6-membered monocyclic heterocyclic ring are fused, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

3. The compound according to claim 2, rR!

.C wherein the ring 1,- 2) is Alll L oC R! R! R' R! N- 5 Ney > A N NSN a N JN N / / Cd, AAJ LF 7 RI? R!? R!? RI? ag, Gp. ay, 1) Oo S = ’ N° ’ 7 or N = wherein all symbols have the same meanings as described in claim 2, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

4. The compound according to claim 2, wherein R' is amino which may be protected, or R'* is NR®R’, in which R® and R’ have the same meanings as described in the claim 2, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

5S. The compound according to claim 2, wherein Z* is -NR’-, in which R® has the same meaning as described in claim 2, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

6. The compound according to claim 2, wherein Z* is -CR*R’*-, in which R*® and R* are taken together to represent C2-5 alkylene in which one carbon atom may be substituted with one oxygen atom, nitrogen atom or sulfur atom which may be oxidized, wherein the C2-5 alkylene may be substituted with a substituent(s), a salt thereof, an N- oxide thereof, a solvate thereof or a prodrug thereof.

7. The compound according to claim 2, which is represented by formula (I-A- 3):

® i” es N (alin) EA) “yon R tn RIA . -C : wherein 7a) 1s ol oc N RIA RIA Gc! RA co RIA 2 2 al N-N © al Non al 74 N N © al 72 NS CAS TAS TRA OTA N N N™°N N™°N G1 ’ G4! ’ or R'* represents amino which may be protected with 1 or 2 of C1-15 alkyl which may be substituted, G*'s each independently represents a hydrogen atom, a halogen atom, CFs, OCF;, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substituted with 1 or 2 substituents selected from a halogen atom, CF; and hydroxyl, G? represents a hydrogen atom, C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted, hydroxyl which may be protected, cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl, a halogen atom, CF;, or cyano; and other symbols have the same meanings as in claim 2, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

8. The compound according to claim 2, which is represented by formula (I-A- 4): Rl*-A 6 N SN Cl NE ba.

® ® R!2-A wherein “D0 is (alin) NT po RI*A G2 RIA G2 Rlz-A RA G? ey = LT eS) N N N N™°N G2 ’ G2 pe or R'*# represents NR¥R’*, in which one of R® and R** represents C1-15 alkyl which may be substituted with the substituent group 1 and another represents a hydrogen atom or C1-15 alkyl which may be substituted with the substituent group 1, wherein the substituent group 1 has the same meaning as in claim 2; G™*s each independently represents a hydrogen atom, a halogen atom, CFs, OCF;, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, oxy, oxo, or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substituted with 1 or 2 substituents selected from a halogen atom, CF; and hydroxyl; and other symbols have the same meanings as described in claim 2 or 7, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

9. The compound according to claim 2, which is: 1) N°-(2-chloro-4-methoxyphenyl)-6-methyl-N’ N’-dipropylpyrazolo[1,5- a]pyrimidine-5,7-diamine, 2) N°-(2-chloro-4-methoxyphenyl)-N’-(1-ethylpropyl)-6-methylpyrazolo[ 1,5- a]pyrimidine-5,7-diamine, 3) N°-(2-chloro-4-methoxyphenyl)-6-ethyl-N’ N’-dipropylpyrazolo[ 1,5- a]pyrimidine-5,7-diamine, 4) N2-(2-chloro-4-methoxyphenyl)-N*-ethyl-N* N*-dipropyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine-2,4-diamine, (5) N°-(2-chloro-4-methoxyphenyl)-6-methoxy-N’,N’-dipropylpyrazolo[1,5- a]pyrimidine-5,7-diamine, (6) NZ2-allyl-N2-(2-chloro-4-methoxyphenyl)-N* N*-dipropyl-6, 7-dihydro-SH- cyclopenta[d]pyrimidine-2,4-diamine, ©) 6-methyl-N>-[2-methyl-4-(trifluoromethoxy)pheny!}-N’ N’- dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine, 8) N-butyl-N>-(2-chloro-4-methoxyphenyl)-N’-ethyl-6-methylpyrazolo[ 1,5- a]pyrimidine-5,7-diamine,

©) N° -(2-ethyl-4-methylphenyl)-6-methyl-N’ N’-dipropylpyrazolo[1,5- aJpyrimidine-5,7-diamine, (10) 6-methoxy-N’ -(4-methyl-2-vinylphenyl)-N’ N’-dipropylpyrazolo[1,5- a]pyrimidine-S,7-diamine, or (1Y N° -(2-ethyl-4-methylpheny!)-6-methoxy-N’ N"-dipropylpyrazolo[1,5- a]pyrimidine-5,7-diamine.

10. A pharmaceutical composition comprising, as an active ingredient, the compound represented by formula (I-A) according to claim 2, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

11. The pharmaceutical composition according to claim 10, which is a CRF antagonist.

12. The pharmaceutical composition according to claim 10, which is an agent for preventing and/or treating CRF mediated diseases.

13. The pharmaceutical composition according to claim 12, wherein the CRF mediated diseases are psychiatric and neurologic disorders or digestive diseases.

14. The pharmaceutical composition according to claim 13, wherein the psychiatric and neurologic disorders or the digestive diseases are mood disorders, anxiety disorders, stress-related disorders, eating disorders, symptom caused by psychotropic substance or dependency thereon, organic mental disorder, schizophrenic disorder, attention-deficit hyperactivity disorder or irritable bowel syndrome.

15. The pharmaceutical composition according to claim 14, wherein the psychiatric and neurologic disorders or the digestive diseases are depression, mood disorders, eating disorders, drug addiction, drug dependency or irritable bowel syndrome.

16. A medicament comprising a combination of the compound represented by formula (I-A) according to claim 2, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof with at least one selected from a tricyclic antidepressant, a tetracyclic antidepressant, a monoamine oxidase inhibitor, a serotonin and noradrenaline reuptake inhibitor, a selective serotonin reuptake inhibitor, a serotonin reuptake inhibitor, a psychoanaleptic, an antianxiety agent, an antipsychotic agent, a mitochondrial benzodiazepine receptor ligand, an NK1 antagonist, a gastrointestinal promotility agent, a

) PCT\JP2004\013386 R 5-HT; antagonist, a S-HT4 agonist, an anticholinergic agent, an antidiarrheal drug, a lapactic and an autonomic modulating agent.

17. Use of the compound represented by formula (I), a salt thereof, an N- oxide thereof, a solvate thereof or a prodrug thereof for the manufacture of a CRF antagonist: x RN AllB ; Mm LS R’ N Zz wherein all symbols have the same meanings as described in claim 1.

18. Use of the compound represented by formula (I), a salt thereof, an N- oxide thereof, a solvate thereof or a prodrug thereof for the manufacture of a CRF mediated disease: R! GC R All 5) (I-A) L-oC -R® N yA wherein all symbols have the same meanings as described in claim 2.

19. Use according to claim 18 wherein the CRF mediated diseases are psychiatric and neurologic disorders or digestive diseases.

20. Use according to claim 19, wherein the psychiatric and neurologic disorders or the digestive diseases are mood disorders, anxiety disorders, stress- related disorders, eating disorders, symptom caused by psychotropic substance or dependency thereon, organic mental disorder, schizophrenic disorder, attention-deficit hyperactivity disorder or irritable bowel syndrome.

21. Use according to claim 20, wherein the psychiatric and neurologic disorders or the digestive diseases are depression, mood disorders, eating disorders, drug addiction, drug dependency or irritable bowel syndrome.

22. A compound according to any one of claims 1 to 9, substantially as herein described with reference to any of the examples and as illustrated. -117 - AMENDED SHEET

PCT\JP2004\013386

23. A composition according to any one of claims 10 to 15, substantially as herein described with reference to any of the examples and as illustrated.

24. A medicament according to claim 16, substantially as herein described with reference to any of the examples and as illustrated.

25. Use according to any one of claims 17 to 21, substantially as herein described with reference to any of the examples and as illustrated. -118 - AMENDED SHEET